Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption

Article Article scientifique Article Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption eng 2019 author Arnold Yvonne Elisabeth 802500 author Thorens Julien author Bernard Stéphane author Kalia Yogeshvar 0000-0001-9049-5489 503798 10.3390/pharmaceutics11030139 30901927 1999-4923 Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, Papp,pig, were compared to the permeability coefficients determined in humans in vivo, Peff,human. Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published Peff,human values were used to test the system. The initial experiments measured Papp,pig for each drug after application in a Krebs⁻Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between Peff,human and Papp,pig. Differences in the segmental Papp,pig of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased Papp,pig across the ileum of the P-gp substrates cimetidine and ranitidine (p < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased Papp,pig of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4. CYP3A4 P-gp Ussing chamber Biorelevant media Intestinal permeability Regional drug absorption. Dewey 615 31 Section des sciences pharmaceutiques 17 false Pharmaceutics 11 3 5a651513-46e1-4661-ba2a-d4274aac831c Article (Published version) Public 19_Arnold_Pharmaceutics.pdf 807258 application/pdf CC BY openAccess Faculté des sciences / Section des sciences pharmaceutiques

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption	Pharmaceutics			2019	303	571

Archive ouverte UNIGE

Arnold, Yvonne Elisabeth